DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1, 3, 4, 6-18, 20, 22, 29, and 33-35 as preliminarily amended are currently pending and under consideration on the merits.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 4, 6-18, 20, 22, 29, and 33-35 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the final bioreactor", but there is insufficient antecedent basis for this limitation in the claim because the preceding elements of the claim do not manipulatively or structurally set forth any “final bioreactor”. It is unclear how the claimed “final bioreactor” does and does not Correction is required.
Claims 6, 13, and 20 depends from claim 1 and recite “bioreactor”, which blurs the metes and bounds of this claim because it is not clear if the claims are referring to the “bioreactor” or the “final bioreactor” of claim 1. Correction is required.
Because claims 3, 4, 6-18, 20, 22, 29, and 33-35 depend from claim 1 and do not resolve the point of confusion, these claims must be rejected with claim 1 as indefinite.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 4, 6-18, 20, 22, 29, and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Hiller et al. (US 2019/0031997; provided in the IDS dated 8/25/2025).
Hiller teaches a method for culturing cells to produce a recombinant protein, comprising: 1) initiating a culture in a bioreactor at a culture volume that is at least 50% of the final bioreactor working volume (Example 2 at ¶0080), 2) inoculating the culture with CHO cells engineered to express the recombinant IgG antibody (Example 2, the title of this subheading just before ¶0080, and noting antibody production at Fig. 20 and ¶0101), 3) perfusing the culture at one or more perfusion rates of less than or equal to 0.5 culture volumes/day (V/d) until the culture reaches one or more desired target criteria (Example 2, at Fig. 12 with the V/d being less than 0.5 for days 1-2 of culture and the target criteria being protein concentration at about 50-100 mg/L as set forth in Fig. 20), 4) increasing the culture volume to a final culture volume (Example 2 at ¶0080 and noting being operated a similar volume ration as Example 1, and ¶0067 wherein transferring about 19% of the volume of the initial/starting N-1 perfusion bioreactor to the second/final production CSTR bioreactor), and 5) once the final culture volume is achieved, perfusing the culture at one or more perfusion rates of less than or equal to 0.5 culture volumes/day (V/d) for less than 5 days in the N-1 bioreactor (Example 1, at ¶0068 and Fig. 3), reading in-part on claim 1 and reading on claims 33 and 35. IN a separate embodiment, Hiller teaches a 1:1 volume ratio between the culture bioreactor and the production/CSTR bioreactor of 1:1 (¶0054), reading on the culture volume that is at least 50% relative to any final/production bioreactor working volume of claim 1 and reading in-part on claim 3. Hiller teaches daily average perfusion rates (i.e. RV/day) of 1.76 or 3.6 depending upon the target criteria of 80 x 106 cells/ml or 40 x 106 cells/ml in the N-1 bioreactor (Fig. 12, ¶0025, and ¶0085), reading in-part on the second perfusing step of claims 1, and reading in-part on claims 11 and 12, 17, and 18. Hiller teaches that the cells control and ramp up their own perfusion rate and simultaneous removal of cell-free permeate as a function of the pH of the cell culture media (¶0085) and a set predetermined pH value being 7 or in the range of 6.8-7.4 (¶0071), reading in-part on the second perfusing step of claims 1, reading in-part on claims 11, 12, 17, and 18, and reading on the differential perfusion and associated generic feed and permeate rates of claims 16 and 20. Hiller teaches a cell bleed rate for the N-1 bioreactor of 0.4 volumes removed per day (¶0068), equating to the 60% working volume of claims 3 and 20. Hiller teaches an initial cell density of 1.2 x 106 cells/ml in the N-1 bioreactor (Table 5), reading on claim 4. Hiller teaches wherein the bioreactor is operated in batch mode for up to 24 hours following inoculation (Fig. 12, noting a zero perfusion on day 1 and non-zero perfusion rate on day 2, and ¶0085, noting the N-1 bioreactors are initially operated only in batch mode without perfusion), reading on claim 6. Hiller teaches that wherein the culture is in a growth phase prior to the increase in culture volume to the final culture volume (e.g. exponential growth in the N-1 bioreactor at days 1-5), reading on claim 7 and the embodiment of exponential growth for days 1-3 (i.e. 24-72 hours) post-inoculation for claim 15. Hiller teaches the duration of the growth phase is less than or equal to 60% of the culture duration; and/or the culture temperature during the growth phase is 35°C to 37°C (Table 5 for a culture temperature of 36.5 °C, and Fig. 2A for the growth phases being the exponential increase in viable cell density being the first 5 days for the N-1 bioreactor (the white squares) and the first 6 days for the CSTR bioreactor (the black squares), reading on claims 8 and 10, the CSTR bioreactor as the production reactor for claim 9, and claim 22. Hiller teaches a target criteria comprising a cell density of 100-350 x 105 cells/ml (i.e. 10-35 x 106 cells /ml) (Fig. 2A, the CSTR bioreactor (the black squares) starting at about day 20), reading on claims 13 and 14. Hiller teaches harvest/recovery and purification of the recombinant secreted therapeutic protein by immunoaffinity or ion-exchange columns (¶0066), reading on claim 29. Hiller teaches an antibody fragment as a species of recombinant protein (¶0065), reading on claim 34.
Regarding claim 1, Hiller does not teach a second step of perfusing the culture at one or more perfusion rates of less than or equal to 0.5 culture volumes/day (V/d) until the culture is terminated or harvested. Regarding claim 3, Hiller does not teach wherein the culture is initiated at a culture volume that is 60% to 70% of the final bioreactor working volume. Regarding claim 11, Hiller does not teach wherein the culture is perfused at one or more perfusion rates of 0.05 V/d to 0.5 V/d until the culture reaches one or more desired target criteria, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same; and/or once the final culture volume is achieved, the culture is perfused at one or more perfusion rates of 0.05 V/d to 0.5 V/d until the culture is terminated or harvested, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same. Regarding claim 12, Hiller does not teach wherein the culture is perfused at one or more perfusion rates of 0.10 V/d to 0.25 V/d until the culture reaches one or more desired target criteria, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same; and/or once the final culture volume is achieved, the culture is perfused at one or more perfusion rates of 0.10 V/d to 0.25 V/d until the culture is terminated or harvested, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same. Regarding claim 17, Hiller does not teach wherein at least one of the one or more feed rates is less than or equal to 0.50 V/d and at least one of the one or more permeate rates is less than or equal to 0.20 V/d, wherein each of the one or more feed rates is greater than the contemporaneous permeate rate. Regarding claim 18, Hiller does not teach … Regarding claim 20, Hiller does not teach wherein at least one of the one or more feed rates is less than or equal to 0.40 V/d and at least one of the one or more permeate rates is less than or equal to 0.15 V/d, wherein each of the one or more feed rates is greater than the contemporaneous permeate rate.
However, optimization within prior art conditions or through routine experimentation will generally not support patentability absent a showing of criticality of the claimed range(s) to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. In this case and regarding claims 1, 11, 12, 17, and 18, Hiller clearly teaches that the daily average perfusion rates (i.e. RV/day) is a known result-effective variable depending upon the desired cell density in Hiller’s methods of making recombinant protein(s) from mammalian cells as cited above. Regarding claim 3, Hiller clearly teaches that a 1:1 volume ratio between the culture bioreactor and the production/CSTR bioreactor of 1:1 is result-effective to operably produce recombinant proteins in the mammalian cell culture methods as cited above. Thus, the burden is shifted back to establish criticality of the culture volumes/day range by objective evidence.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4, 7-15, 29, 33, and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, and 10 of U.S. Patent No. 11,104,875 (Reference A) in view of Kudugunti (US 2018/0148677; Reference B).
Claim 1 of the ‘875 patent claims a method of producing a protein of interest, comprising: (a) culturing cells comprising a gene that encodes the protein of interest (e.g. a recombinant protein) in a culture bioreactor (N-1 bioreactor); (b) inoculating a production bioreactor (N bioreactor) with cells obtained from step (a); and (c) culturing the cells in the production bioreactor under conditions that allow production of the protein of interest (e.g. target criteria), wherein the inoculation in step (b) is by transferring cells from the culture bioreactor to the production bioreactor, wherein the cell transfer is by cell bleed in semi-continuous mode comprising the cell transfer once at every period of time from 2 minutes to 24 hours or any interval there between, reading in-part on instant claim 1. Claim 5 of the ‘875 patent claims wherein volume ratio of the culture bioreactor to the production bioreactor is about 1:1 to about 1:20, reading on the initiating step of instant claim 1. Claim 10 of the ‘875 patent claims C.H.O. cells, reading on instant claim 35. The ’875 patent claims generic harvesting at claim 2, reading in-part on instant claim 29. The ’875 patent claims wherein the culture is in a production phase following the increase in culture volume to the final culture volume (claim 5), reading on instant claim 9.
Regarding claim 1, the ‘875 patent does not claim increasing the culture volume to a final culture volume; and once the final culture volume is achieved, perfusing the culture at one or more perfusion rates of less than or equal to 0.5 culture volumes/day (V/d) until the culture is terminated or harvested. Regarding claim 11, the ‘875 patent does not claim wherein the culture is perfused at one or more perfusion rates of 0.05 V/d to 0.5 V/d until the culture reaches one or more desired target criteria, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same; and/or once the final culture volume is achieved, the culture is perfused at one or more perfusion rates of 0.05 V/d to 0.5 V/d until the culture is terminated or harvested, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same. Regarding claim 12, the ‘875 patent does not claim wherein the culture is perfused at one or more perfusion rates of 0.10 V/d to 0.25 V/d until the culture reaches one or more desired target criteria, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same; and/or once the final culture volume is achieved, the culture is perfused at one or more perfusion rates of 0.10 V/d to 0.25 V/d until the culture is terminated or harvested, wherein the feed rate(s) and the contemporaneous permeate rate(s) are the same.
Kudugunti teaches methods and systems of harvesting a cell product from a cell culture by culturing cells in a fluid medium until the cells have produced a cell product at a harvest concentration are disclosed (Abstract), such as with CHO cells (¶0086). Kudugunti teaches an extracting and refilling volume less than about 0.5 vessel volume exchanged per day (i.e. VVD) (¶0014), reading on claim 1, 11, and 12.
Regarding instant claims 1, 11, and 12, it would have been obvious to a person of ordinary skill in the art before the invention was filed to further perfuse the method of ‘875 patent at a perfusion rate of less than or equal to 0.5 volumes per day and having the perfusion rate (e.g. refilling volume) and permeate rate (e.g. extracting volume) be the same as either 0.05 V/d to 0.5 V/d or 0.10 V/d to 0.25 V/d in view of Kudugunti. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Kudugunti and the ‘875 patent are directed towards methods of producing recombinant protein(s) of interest with CHO cells. The skilled artisan would have been motivated to do so because Kudugunti teaches an extracting and refilling volume less than about 0.5 vessel volume exchanged per day (i.e. VVD), and so would predictably yield known VVD exchange rate(s) in the methods of the ‘875 patent; “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396
Kudugunti teaches inoculating with 5-7E6 (i.e. x 106) cells/ml (¶0086), reading on instant claim 4. Kudugunti teaches wherein the culture is in a growth phase prior to the increase in culture volume to the final culture volume and wherein the one or more desired target criteria is a cell density of 100 x 105 cells/mL to 350 x 105 cells/mL (i.e. 10-35 x 106 cells/ml; Fig. 3 and ¶0088), reading on claims 7 and 14. Kudugunti teaches wherein the duration of the growth phase is less than or equal to 60% of the culture duration; and/or the culture temperature during the growth phase is 35°C to 37°C (Fig. 9, ¶0035, and ¶0099 for a linear growth phase, and Table 3 for a culture temperature of 37°C), reading on instants claim 8 and 10. Kudugunti teaches wherein the one or more desired target criteria is time post-inoculation, wherein the time post- inoculation is 24 hours to 72 hours (e.g. the linear growth of the cells at days 1-3 in Fig. 3), reading on claim 15. Kudugunti teaches a method further comprising harvesting the recombinant protein; processing the recombinant protein through one or more unit operations; and obtaining an isolated, purified recombinant protein by column purification (¶0005), reading on instant claim 29. Kudugunti teaches wherein the recombinant protein is an antibody (Table 2), reading on instant claim 33
Regarding instant dependent claims 4, 7-15, 29, and 33, although the claims at issue are not identical, they are not patentably distinct from each other because Kudugunti is coextensive to these additional limitations and so it would have been obvious to a person of ordinary skill in the art before the invention was filed to further modify the claims of the ‘875 patent because combining separate steps taught as useful in a method into a singular method must be held as prima facie obvious, as each step is taught separately useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Conclusion
No claims are allowed. No claims are free of the art.
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/Sean C. Barron/Primary Examiner, Art Unit 1653